Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies

Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24 , respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT , no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy

Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis

Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six miR-124 alleles in human induced pluripotent stem cells. Upon neuronal induction, miR-124-deleted cells underwent neurogenesis and became functional neurons, albeit with altered morphology and neurotransmitter specification. Using RNA-induced-silencing-complex precipitation, we identified 98 high-confidence miR-124 targets, of which some directly led to decreased viability. By performing advanced transcription-factor-network analysis, we identified indirect miR-124 effects on apoptosis, neuronal subtype differentiation, and the regulation of previously uncharacterized zinc finger transcription factors. Our data emphasize the need for combined experimental- and system-level analyses to comprehensively disentangle and reveal miRNA functions, including their involvement in the neurogenesis of diverse neuronal cell types found in the human brain

A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy

Members of the AAA+ superfamily of ATPases are involved in the unfolding of proteins and disassembly of protein complexes and aggregates. ATAD1 encoding the ATPase family, AAA+ domain containing 1-protein Thorase plays an important role in the function and integrity of mitochondria and peroxisomes. Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2. Using whole-exome sequencing, we identified a homozygous frameshift mutation in the last exon of ATAD1 [c.1070_1071delAT; p.(His357Argfs*15)] in three siblings who presented with a severe, lethal encephalopathy associated with stiffness and arthrogryposis. Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes. Atad1−/− neurons expressing Thorase mutantHis357Argfs*15 display reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane. Taken together, our molecular and functional analyses identify an activating ATAD1 mutation as a new cause of severe encephalopathy and congenital stiffness

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

Background: Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death. Methods: We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed. Results: Two terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient. Conclusion: Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes

Isospin-tracing: A probe of non-equilibrium in central heavy-ion collisions

Four different combinations of $^{96}_{44}$Ru and $^{96}_{40}$Zr nuclei, both as projectile and target, were investigated at the same bombarding energy of 400$A$ MeV using a $4 \pi$ detector. The degree of isospin mixing between projectile and target nucleons is mapped across a large portion of the phase space using two different isospin-tracer observables, the number of measured protons and the ${\rm t}/^{3}{\rm He}$ yield ratio. The experimental results show that the global equilibrium is not reached even in the most central collisions. Quantitative measures of stopping and mixing are extracted from the data. They are found to exhibit a quite strong sensitivity to the in-medium (n,n) cross section used in microscopic transport calculations.Comment: 4 pages RevTeX, 3 figures (ps files), submitted to Phys. Rev. Let

Identification of baryon resonances in central heavy-ion collisions at energies between 1 and 2 AGeV

The mass distributions of baryon resonances populated in near-central collisions of Au on Au and Ni on Ni are deduced by defolding the $p_t$ spectra of charged pions by a method which does not depend on a specific resonance shape. In addition the mass distributions of resonances are obtained from the invariant masses of $(p, \pi^{\pm})$ pairs. With both methods the deduced mass distributions are shifted by an average value of -60 MeV/c$^2$ relative to the mass distribution of the free $\Delta(1232)$ resonance, the distributions descent almost exponentially towards mass values of 2000 MeV/c^2. The observed differences between $(p, \pi^-)$ and $(p, \pi^+)$ pairs indicate a contribution of isospin $I = 1/2$ resonances. The attempt to consistently describe the deduced mass distributions and the reconstructed kinetic energy spectra of the resonances leads to new insights about the freeze out conditions, i.e. to rather low temperatures and large expansion velocities.Comment: 30 pages, 13 figures, Latex using documentstyle[12pt,a4,epsfig], to appear in Eur. Phys. J.

Direct comparison of phase-space distributions of K- and K+ mesons in heavy-ion collisions at SIS energies - evidence for in-medium modifications of kaons ?

The ratio of K- to K+ meson yields has been measured in the systems RuRu at 1.69 A GeV, Ru+Zr at 1.69 A GeV, and Ni+Ni at 1.93 A GeV incident beam kinetic energy. The yield ratio is observed to vary across the measured phase space. Relativistic transport-model calculations indicate that the data are best understood if in-medium modifications of the kaons are taken into account.Comment: 14 pages including 3 figure

Differential directed flow in Au+Au collisions

We present experimental data on directed flow in semi-central Au+Au collisions at incident energies from 90 to 400 A MeV. For the first time for this energy domain, the data are presented in a transverse momentum differential way. We study the first order Fourier coefficient v1 for different particle species and establish a gradual change of its patterns as a function of incident energy and for different regions in rapidity.Comment: 5 pages, Latex, 5 eps figures, accepted for publication in Phys. Rev. C (Rapid Communications). Data files available at http://www-linux.gsi.de/~andronic/fopi/v1.htm

Sideward flow of K+ mesons in Ru+Ru and Ni+Ni reactions near threshold

Experimental data on K+ meson and proton sideward flow measured with the FOPI detector at SIS/GSI in the reactions Ru+Ru at 1.69 AGeV and Ni+Ni at 1.93 AGeV are presented. The K+ sideward flow is found to be anti-correlated (correlated) with the one of protons at low (high) transverse momenta. When compared to the predictions of a transport model, the data favour the existence of an in-medium repulsive K+ nucleon potential.Comment: 16 pages Revtex, 3 ps-figures, submitted to Phys. Lett.

Transition from in-plane to out-of-plane azimuthal enhancement in Au+Au collisions

The incident energy at which the azimuthal distributions in semi-central heavy ion collisions change from in-plane to out-of-plane enhancement, E_tran, is studied as a function of mass of emitted particles, their transverse momentum and centrality for Au+Au collisions. The analysis is performed in a reference frame rotated with the sidewards flow angle, Theta_flow, relative to the beam axis. A systematic decrease of E_tran as function of mass of the reaction products, their transverse momentum and collision centrality is evidenced. The predictions of a microscopic transport model (IQMD) are compared with the experimental results.Comment: 32 pages, Latex, 22 eps figures, accepted for publication in Nucl. Phys.